Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex

Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gen...

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Bibliographic Details
Published in:Genes & development 2008-05, Vol.22 (10), p.1397-1409
Main Authors: Kajimura, Shingo, Seale, Patrick, Tomaru, Takuya, Erdjument-Bromage, Hediye, Cooper, Marcus P, Ruas, Jorge L, Chin, Sherry, Tempst, Paul, Lazar, Mitchell A, Spiegelman, Bruce M
Format: Article
Language:English
Subjects:
3T3 Cells
3T3-L1 Cells
Adipose Tissue, Brown - metabolism
Adipose Tissue, Brown - physiology
Adipose Tissue, White - metabolism
Adipose Tissue, White - physiology
Alcohol Oxidoreductases - metabolism
Alcohol Oxidoreductases - physiology
Animals
Cell Differentiation - genetics
Chlorocebus aethiops
COS Cells
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Gene Expression Regulation
Genes, Regulator
Mice
Models, Biological
Multiprotein Complexes - physiology
Phosphoproteins - metabolism
Protein Binding
Research Paper
Transcription Factors - metabolism
Transcription Factors - physiology
Transcription, Genetic
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Summary:Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gene expression, while suppressing the expression of genes selective for white fat cells. To determine the mechanisms regulating this switching of gene programs, we purified native PRDM16 protein complexes from fat cells. We show here that the PRDM16 transcriptional holocompex contains C-terminal-binding protein-1 (CtBP-1) and CtBP-2, and this direct interaction selectively mediates the repression of white fat genes. This repression occurs through recruiting a PRDM16/CtBP complex onto the promoters of white fat-specific genes such as resistin, and is abolished in the genetic absence of CtBP-1 and CtBP-2. In turn, recruitment of PPAR-gamma-coactivator-1alpha (PGC-1alpha) and PGC-1beta to the PRDM16 complex displaces CtBP, allowing this complex to powerfully activate brown fat genes, such as PGC-1alpha itself. These data show that the regulated docking of the CtBP proteins on PRDM16 controls the brown and white fat-selective gene programs.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1666108